Late onset neurodegenerative diseases (LOND) are complex, heterogeneous diseases. These invariably progressive diseases have overlapping clinical and neuropathological manifestations Most of the familial cases with simple autosomal dominant inheritance patterns are caused by a genetic mutation in one of several recently identified genes The familial cases together explain only a small proportion of all cases, especially in late life when incidence rates are highest. Despite a tremendous progress in understanding of the origin of genetically determined cases of LOND, the etiology of the sporadic cases that represent the majority of all cases remains unknown. It is universally accepted that sporadic cases are not genetic in nature. They are believed to be caused by a combination of genes and environment. Despite significant efforts of numerous research groups in academia and industry what causes the majority of the cases with LOND is not known. At present, no environmental factor has been shown to be the cause of any of these diseases. Moreover, there is no coherent conceptual approach to the identification of these causes. Hypothesis: Age related neurodegenerative diseases are transmissible. The basic design of the proposed experiments and the analysis of the data are not constrained by a speculation on the etiology or a particular transmissible agent that might cause a specific LOND. Rather, we propose to approach the question of etiologies using an experimental paradigm that proved successful in discoveries of conventional but challenging etiological agents of various infectious diseases, as well as of the unconventional infectious agents that we now call prions. While extensive efforts to demonstrate transmissibility were carried out with several LONDs decades ago with entirely negative results, the endpoints employed were limited. The most essential aspect of our proposed research involves a renewed search for evidence of transmissibility of LONDs utilizing state of the art molecular and immunohistochemical methods to analyze a unique large collection of fixed brains tissues of nonhuman primates inoculated with tissues from patients with LONDs, and a large collection of frozen brain tissues of the very same patients that were used in these original transmission studies in the 1960s - 1980s. Our approach will utilize endpoints that are based on the detection of defined proteins and ultimately nucleic acids (if they are involved) with or without functional impairments of inoculated animals or obvious brain lesions. Our recent pilot studies have already demonstrated that this approach is likely to work. In order to determine if a transmissible agent contains a specific nonhuman nucleic acid we will use an unbiased metagenomic approach to analyze patients'brain tissues. If transmissibility of one or more of the LONDs is established, research on their pathogeneses will be dramatically altered and totally new avenues to prevention, intervention, and treatment will become apparent. PUBLIC HEALTH RELEVANCE: The main research objective of the proposed research is to determine the cause of diseases like Alzheimer's disease and similar diseases that cause dementia in older people. Much of the progress in our understanding of the origin of these so called neurodegenerative diseases comes from genetics. A number of genes that cause inherited forms of these diseases have been discovered. However, the cause of the vast majority of cases is unknown. They are sporadic, not inherited and they are not caused by the genes. It is universally accepted that the primary cause of these diseases is environmental. Over the years the idea of an infectious origin has been frequently investigated. However, despite occasional claims of success, no experimental proof of transmission from human cases to animals were obtained with a notable exception of prion diseases such as Creitzfeldt-Jakob disease in man and scrapie and mad cow disease in animals. Researchers in the 1960s-1980s inoculated thousands of monkeys and other laboratory animals in search for an infectious agent in neurodegenerative diseases. However, no signs of transmission of an infectious agent from human to animals were detected. We propose to use new tools and methods that have been developed since the time of the original studies and reanalyze the archival tissues from these experiments. We already have evidence that such approach works in cases of Alzheimer's disease. Determination of transmissibility will have a tremendous significance and will change forever our understanding of these diseases. It will also open new approaches and new opportunities in studying the pathological processes and in the development of new treatments of neurodegenerative diseases.